Clinicogenomic Landscape of <i>MTAP</i>-Deleted Thoracic Malignancies Across US and Japanese Nationwide Cohorts: Impact of Concurrent <i>CDKN2A</i> Alterations and Driver Mutations.

Abstract

PURPOSE: Methylthioadenosine phosphorylase (MTAP) deletion represents a promising therapeutic vulnerability through synthetic lethality. However, the clinical and molecular context of MTAP-deleted thoracic tumors, particularly with respect to actionable oncogenic drivers and immune checkpoint inhibitor efficacy, remains incompletely defined across diverse populations. METHODS: We analyzed clinicogenomic data from two nationwide cohorts: AACR Project GENIE (United States; n = 11,091 evaluable samples) and Center for Cancer Genomics and Advanced Therapeutics (C-CAT; Japan; n = 4,851). MTAP copy number was assessed in lung, pleural, and thymic tumors. We evaluated histology-specific prevalence, comutational patterns, associations with actionable genomic alterations, tumor mutational burden (TMB), and overall survival (OS) in selected molecular subgroups. RESULTS: In lung cancer, MTAP deletion occurred at comparable frequencies between adenocarcinoma and squamous cell carcinoma within each cohort (GENIE: 8.1% v 9.8%; C-CAT: 19.6% v 16.5%) but was rare in small cell lung cancer (GENIE: 1.0%; C-CAT: 1.9%). In thymic tumors, MTAP deletion was observed predominantly in thymic carcinoma and was uncommon in thymoma. MTAP deletion was strongly associated with CDKN2A/B deletions and was rare in their absence. MTAP deletion frequently coexisted with actionable driver alterations, including EGFR mutations, ALK fusions, and ERBB2 alterations. A robust inverse association with RB1 mutations was observed in both cohorts. Although MTAP deletion appeared associated with lower TMB (P < .01) and shorter OS in EGFR-mutated lung cancer (median 18.5 v 31.4 months, P < .01), these associations were largely attributable to enrichment of oncogenic drivers and concurrent CDKN2A loss, respectively. CONCLUSION: MTAP-deleted thoracic tumors exhibit reproducible clinical and molecular features across populations. Our findings support the rational, globally applicable development of MTAP-targeted synthetic lethal strategies in thoracic malignancies, particularly in combination with molecular targeted agents.